[PAGID] 6 mo old with enteropathy and few B cells

[MacGinnitie, Andrew]

Our immunology service is consulting on an interesting patient I'm having trouble understanding and I'd appreciate any input

Patient is a 6 mo old girl transferred to our hospital after a month in an outside hospital for failure to thrive and diarrhea.  She developed Klebsiella pneumonia and respiratory failure requiring intubation which was the proximate cause of transfer.  Intestinal biopsy showed autoimmune enteropathy; liver biopsy showed some fatty changes but hepatocytes themselves were normal and no evidence of autoimmunity. Stool cultures all negative

No significant infectious history prior to the Klebsiella

PE without rash, erythema or desquamation.  Really only remarkable for small size, intubation and some increased breath sounds.

Immune studies to date include

CBC on transfer showed ALC of 1320, and 440 eos in setting of increased polys with left shift.  Current ALC about 2000 and eos 0, but on steroids.

Multiple IgA < or = 10; IgM all < 25
Multiple IgGs <40.  Several g/kg of IVIG have not been very successful at raising the IgG level, although 2g/kg raised the level to 300 right after but down to 100 today (24 hours later) suggesting she is losing quickly.

Lymphocyte subsets include

CD3+  2489
CD3+/CD4+ 1940
CD3+/CD8+  577
CD19+  46
CD16/CD56+ 111

so very low B cells, slighly low NK and CD3CD8 cells

We also had them stain for CD45RA and CD62L and this showed  >90% of CD4 cells were CD45RA/CD62L+ (naive)

Proliferation studies are pending as are repeat subsets.

In summary, 6 mo old girl with chronic diarrhea probably secondary to autoimmune enteropathy, with lack of B cells or evidence of immunoglobulin synthesis.

I've thought of Omenn's but she lacks characteristic skin findings, and I wouldn't expect a normal number of naïve T cells.  

I also considered IPEX, but she's a girl and only has autoimmunity in the gut that we can see.

Finally I thought about an autosomal recessive agammaglobulinemia with a second process causing the autoimmune enteropathy and protein losing enteropathy, but that isn't very elegant.

I'd appreciate any input on differential or further testing.  Immunosuppression with steroids and cyclosporine was started yesterday.

Andy

Andrew J. MacGinnitie MD PhD 
Assistant Professor of Pediatrics 
Division of Pulmonary Medicine, Allergy and Immunology 
Children's Hospital of Pittsburgh 
3705 Fifth Ave, Pittsburgh, PA 15213 
andrew.macginnitie at chp.edu 
412/692-8903 (office) 412/692-8499 (fax)



-----Original Message-----
From: pagid-bounces at list.clinimmsoc.org on behalf of Kathleen E. Sullivan
Sent: Thu 6/28/2007 7:15 AM
To: pagid at list.clinimmsoc.org
Subject: Re: [PAGID] Welcome to the "PAGID" mailing list
 
A form of LAD perhaps?

Kathleen E. Sullivan MD PhD
Chief, Division of Allergy and Immunology
Professor of Pediatrics
The Children's Hospital of Philadelphia
(p) 215-590-1697
(f) 267-426-0363


On Jun 27, 2007, at 6:41 PM, Dr Joanne Smart wrote:


> Dear All,

>

> Would welcome any suggestions about the following case (currently  

> an inpatient at the Royal Children's Hospital Mebourne Australia):

>

> Essentially this is a 6 week old female infant born to  

> consanguineous Afghanistan parents who presents with presumed  

> sepsis, diarrhea, hepatosplenomegaly, exfoliating dermatitis,  

> profound eosinophillia and thrombocytopenia.

>

> This occurs in the context of a sister, Karima, who died at the age  

> of 5 months in Kentucky with a similar presentation in December  

> 2005.  This child was a term baby with an unremarkable perinatal  

> period.  She first became unwell at 4 weeks with vomiting and mild  

> diarrhoea, and was found to have an abnormal lumbar puncture result  

> (?Citrobacter meningitis from discharge summary).  She was treated  

> with 1 week of IV antibiotics with improvement, but ongoing  

> vomiting on discharge.  She was recalled back to the hospital after  

> 1-2 days for a bone marrow aspirate for an apparent blood  

> abnormality, and the parents were reassured that this "wasn't  

> leukaemia". She was given nyastatin, metoclopramide, ranitidine and  

> prednisolone on that occasion.

>

> She continued to have episodic vomiting at home 1-2x/day and  

> deteriorated at 6 weeks of age with increasing diarrhoea, facial  

> oedema, anuria, left focal seizures and respiratory failure. She  

> also had a dry, erythematous and exfoliating rash on presentation,  

> which was later thought to look like ichthyosis by her physicians.  

> Investigations at this stage revealed hypereosinophillia, anaemia,  

> thrombocytopenia, hyponatremia, hypocalcemia and a severe metabolic  

> acidosis. Aspergillous grew from her endotracheal tube, and skin &  

> bone marrow biopsy revealed was apparently inconclusive.  Further,  

> CT brain revealed cerebellar atrophy and bilateral subdural  

> hydromas.  Her treatment included mechanical ventilation,  

> phenobarbitone, amphotericin B and caspofungin. Eventually with no  

> improvement despite 6 weeks of mechanical ventilation we understand  

> care was tragically withdrawn. The consideration at that stage was  

> whether she could have Ommen's, or an undefined hypereosinophllic  

> syndrome.

>

> Furthermore, there was apparently 14-16 maternal grandaunties and  

> granduncles who passed away between the ages of 4 month-2 years  

> from presentations with fever, diarrhoea and rashes. They however  

> lived in a remote village with no medical care and it is uncertain  

> how many in fact have treatment such as antimicrobials available.

>

> Zohra herself was a term baby who was initially well until day 7 of  

> life, when she presented with fevers, irritability, poor feeding  

> and vomiting. Her inflammatory markers were raised (CRP 105, WCC  

> 17, neutrophils 12) and her platelet count dropped to 70 on day 5  

> of admission, but resolved to 188 on discharge.  Lumbar puncture  

> was attempted but unsuccessful. Stool cultures were negative. In  

> total she received 6 days of IV flucloxacillin and gentamicin, and  

> 3 days of IV ceftraixone.

> She then was readmitted at 3 weeks, when she re-presented with  

> fevers, rash and irritability, with no improvement having been  

> treated with oral amoxicillin by her local doctor for 2 days.  Her  

> CSF at that stage revealed 10 polymorphs, 810 red blood cells and  

> her CRP was elevated at 79. Cultures of the CSF, urine and blood  

> were negative, and she received 4 days of IV cefotaxime, penicillin  

> and gentamicin before being discharged.

>

> She re-presented at the age of 4 weeks with vomiting and diarrhea,  

> but this time without fevers.  No investigations were performed and  

> she was treated for a presumed gastroenteritis with nasogastic  

> rehydration. She was then transferred to Royal Children's Hospital  

> Neonatal Unit for ongoing weight loss.  She had an initial severe  

> metabolic acidosis (pH 7.09, HCO3- 3, base excess -24; anion gap  

> 19; lactate 1.6 normal) and received fluid resuscitation and  

> commencement of IV antibiotics.  As an inpatient she progressively  

> became unwell with development of an exfoliating dermatitis and  

> temperature instability.

> Her investigations to date reveals:

> Full blood count

> Normocytic anaemia (Hb 85-100g/L) - presumably partly contributed  

> by multiple blood tests taken and haemodilution from fluid  

> resuscitation

> Leucocytosis (WCC 33-50x109/L) with fluctuating neutrophillia  

> (8-12x109/L), high band count (3.2-7x109/L) and normal lymphocyte  

> counts (7-8x109/L)

> Profound eosinophillia (15-20x109/L)

> Progressive thrombocytopenia (from 500 to 51x109/L)

> Biochemistry

> Progressive hyponatremia (142mmol/L on presentation, dropped to  

> 124mmol/L) and hypokalemia (3mmol/L)

> She was also hypocalcemic (1.75mmol/L) , hypomagnesemic (0.54mmol/ 

> L) hypophosphatemic (0.65mmol/L) and hypoabluminaemic (16g/L)

> Liver function and renal function essentially normal

> Raised stool and renal electrolytes, raising the question of  

> possible renal tubular acidosis

> Cultures

> CSF - negative culture (0 polymorphs, 1 lymphocyte, 0 erythrocytes)

> Urine - negative culture

> Stool - negative culture

> Immune function

> Antibodies

> IgG 4.28 g/L

> IgA <0.07 g/L

> IgM 0.24 g/L

> Lymphocyte markers

> Normal on 2 occasions

> 18/6/07 - Lymphocyte count (4.39x109/L), CD3 74%, CD4 63%, CD8 13%,  

> CD19 24% and NK cells 3%

> 19/6/07 - Lymphocyte count (6.8x109/L), CD3 77%, CD4 66%, CD8 12%,  

> CD19 18% and NK cells 3%.

> Lymphocyte proliferation to PHA

> Done on 2 occasions

> 18/6/07 - 15,986 to 50,657 (Control 39 to 57,241)

> 19/6/07 - 7,595 to 17,291 (Control 17 to 56,281)

> Neutrophil oxidative burst - normal

> Pending - Variable Number Tandem Repeats (VNTR) and HLA typing of  

> Zohra and her parents.

> Other

> Bone marrow aspirate - normal apart from non-diagnostic high  

> eosinophills

> Urine aminoacids - normal

> Imaging

> Abdominal US - no organomegaly

> Cranial ultrasound - bilateral grade 1 supependymal haemorrhages

>

>  Currently she is being managed with total parental nutrition and  

> IV meropenem and vancomycin.  She has been visited by multiple  

> teams including rheumatology, infectious diseases, metabolic  

> physicians, nephrology and gastroenterology.  She is scheduled to  

> have a liver, skin and muscle biopsy soon.

>

>

>

> Zohra's lymphocyte proliferation whilst not normally is not  

> profoundly depressed as you would expect in a child with SCID.   

> Lack of B cells make Ommen's syndrome unlikely.  We are considering  

> the posibilites of maternally engrafted T cells with resultant  

> graft-versus-host disease and are currnetly awaiting results of  

> VNTR's and HLA typing (which will also help rule out bare  

> lymphocyte syndrome).

>

>

>

>

>

>

>

> At 12:03 AM 28/06/2007, you wrote:

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>

> Dr Joanne Smart

> BSc MBBS PhD FRACP

> Clinical Immunologist

> Department of Immunology

> Royal Children's Hospital

> Flemington Rd, Parkville

> VICTORIA, AUSTRALIA 3052

> PH: 61 3 9345 5733

> FAX: 61 3 9345 5764

> email: joanne.smart at rch.org.au




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